Androgens exert powerful effects on the function of the central and peripheral nervous system, modifying the morphology, function, survival and recovery of neurons in many regions. Androgens have been thought to exert their effects exclusively through the androgen receptor, traditionally considered to be a ligand dependent nuclear transcription factor. However, considerable evidence for non-transcriptional effects of gonadal steroid hormones has been in the literature since the late 70's and has accumulated exponentially in recent years, yet the receptors or alternative mechanisms remain largely unknown. This laboratory recently discovered that androgen receptors are present not only in neuronal nuclei, but in axons and dendrites in the mammalian cerebral cortex. This discovery points to the intriguing possibility that androgen receptors have a novel, extranuclear mode of action in the mammalian cortex. The exploratory studies described in this application will provide information essential to generating hypotheses about this potential extranuclear route of androgen action. A straightforward set of experiments will use combinations of histochemical methods along with light microscopic, electron microscopic and confocal microscopic analysis to: 1) Identify the subcellular distribution of androgen receptor immunoreactivity in axons and terminals; 2) Identify the source of androgen receptor immunoreactive axons in the cerebral cortex; and 3) Determine whether the expression of androgen receptors in axons is sexually differentiated and hormonally regulated. Sex differences in a broad range of mental and neurological disorders suggest that androgens are in some cases protective and in others deleterious. Thus, understanding the mechanisms of action of androgens may provide an essential key to understanding and exploiting the cellular and global impact of endogenous and exogenous androgenic ligands on the healthy and diseased nervous system in both men and women.